ABSTRACT The goal of this work is to evaluate the individual-level effectiveness and potential population-level impact of decentralized anti-retroviral therapy programs (DTP) and enhanced social capital to achieve sustained HIV viral suppression among female sex workers (FSW) living with HIV in South Africa. FSW have been shown to bear disproportionate burden of HIV across Southern Africa and to be at high risk of onward HIV transmission given disparities in access to anti-retroviral therapy (ART). These data are consistent across Sub-Saharan Africa (SSA) and highlight an urgent need to minimize disparities in treatment access for FSW living with HIV, and interrupt these large chains of transmission with better uptake and retention in ART programs. The proposed study will first characterize optimal implementation methods for interventions that address underlying barriers to sustained viral suppression through qualitative interviews with key informants, benefactors, and the government. The crux of the proposed aims are to describe the effectiveness and durability of decentralized treatment programs and case management interventions to achieve sustained viral suppression using adaptive implementation strategies tested through a sequential multiple assignment randomized trial (SMART). The SMART will randomize 782 non-virally suppressed FSW living with HIV in Durban, South Africa to one of two experimental conditions including access to decentralized treatment programs (DTP) or DTP and case management interventions and will follow the participants for 18 months, through multiple randomization assignments. Not all FSW will benefit from - or need - the same intervention or intensity to achieve sustained viral suppression. Indeed, it would not be feasible to implement these interventions for all people living with HVI as neither represent current standard of care. However, the adaptive implementation strategies proposed here provide a platform to evaluate multicomponent, graduated, intervention intensity to achieve sustained viral suppression. Finally, we will evaluate the cost-effectiveness of the varying packages of interventions to measure sustainability and scalability of these approaches. The research will be conducted by Johns Hopkins University, in partnership with the TB/HIV Care Association (THCA) and the University of Toronto. We will utilize existing infrastructure and service delivery systems run by THCA in Durban to recruit FSW living with HIV to participate in the trial. Furthermore, health assessment data routinely collected by THCA and the National Health Laboratory Service will be used, in addition to data collected by the study team, to assess treatment outcomes and viral suppression among these women. The study represents an approach to characterize effective strategies to improve HIV treatment outcomes for a population disproportionately burdened by HIV, and leverage these data to model the cost-effectiveness in the context of the generalized HIV epidemic found in South Africa. This study is in line with the new NIH high priorities in terms of describing optimal approaches to ensure retention in ART and also minimizing disparities.